Measurement of cardiac output &amp; blood volume by non-invasive detection of indicator dilution

ABSTRACT

A system for evaluating the cardiovascular system parameters using indicator dilution and non-invasive or minimally invasive detection methods is disclosed. Intravascular indicators are stimulated, and emission patterns detected for computation of cardiac output, cardiac index, blood volume and other indicators of cardiovascular health.

[0001] This application claims priority upon a provisional applicationNo. 60/292,580, which is herein incorporated by reference.

BACKGROUND OF THE INVENTION

[0002] 1. Field of the Invention

[0003] This invention pertains to the detection of parameters ofcardiovascular system of a subject.

[0004] 2. General Background and State of the Art

[0005] Cardiac output is a central part of the hemodynamic assessment inpatients having heart disease, acute hemodynamic compromise orundergoing cardiac surgery, for example. Cardiac output is a measure ofthe heart's effectiveness at circulating blood throughout thecirculatory system. Specifically, cardiac output (measured in L/min) isthe volume of blood expelled by the heart per beat (stroke volume)multiplied by the heart rate. An abnormal cardiac output is at least oneindicator of cardiovascular disease.

[0006] The current standard method for measuring cardiac output is thethermodilution technique (Darovic, G. O. Hemodynamic monitoring:invasive and noninvasive clinical application. 2nd Ed. W. B. Saunders,1995). Generally, the technique involves injecting a thermal indicator(cold or heat) into the right side of the heart and detecting a changein temperature caused as the indicator flows into the pulmonary artery.

[0007] Typically, the thermodilution technique involves inserting aflow-directed balloon catheter (such as a Swan-Ganz catheter) into acentral vein (basilic, internal jugular or subclavian) and guiding itthrough the right atrium and ventricle to the pulmonary artery. Theballoon catheter is typically equipped with a thermistor near its tipfor detecting changes in blood temperature. A rapid injection of a bolusof chilled glucose solution (through a port in the catheter located inthe vena cava near the right atrium) results in a temperature change inthe pulmonary artery detected with the thermistor. The measuredtemperature change is analyzed with an external electronic device tocompute the cardiac output. The algorithm implemented in thiscomputation is typically a variant of the Stewart-Hamilton technique andis based on the theory of indicator mixing in stirred flowing media(Geddes L A, Cardiovascular devices and measurements. John Wiley & Sons.1984).

[0008] Thermodilution measurements of cardiac output are disadvantageousfor several reasons. First, thermodilution is an expensive and invasivetechnique requiring performance in a sterile surgical suite. Second,this procedure has severe risks to the patient such as local infections,septicemia, bleeding, embolization, catheter-induced damage of thecarotid, subclavian and pulmonary arteries, catheter retention,pneumothorax, dysrrhythmias including ventricular fibrillation,perforation of the atrium or ventricle, tamponade, damage to thetricuspid values, knotting of the catheter, catheter transection andendocarditis. Third, only specially-trained surgeons can insert theballoon catheter for thermodilution cardiac output. Last, thermodilutionmeasurements of the cardiac output are too invasive to be performed insmall children and infants.

[0009] Another method used for measuring cardiac output is the dyeindicator dilution technique. In this technique, a known volume andconcentration of indicator is injected into the circulatory flow. At adownstream point, a blood sample is removed and the concentration of theindicator determined. The indicator concentration typically peaksrapidly due to first pass mixing of the indicator and then decreasesrapidly as mixing proceeds in the total blood volume (˜10 seconds; firstpass concentration curve). Further, indicator concentration slowlydiminishes as the indicator is metabolized and removed from thecirculatory system by the liver and/or kidneys (time depending upon theindicator used). Thus, a concentration curve can be developed reflectingthe concentration of the indicator over time. The theory of indicatordilution predicts that the area under the first pass concentration curveis inversely proportional to the cardiac output.

[0010] Historically, indicator dilution techniques have involvedinjecting a bolus of inert dye (such as indocyanine green) into a veinand removing blood samples to detect the concentration of dye in theblood over time. For example, blood samples are withdrawn from aperipheral artery at a constant rate with a pump. The blood samples arepassed into an optical sensing cell in which the concentration of dye inthe blood is measured. The measurement of dye concentration is based onchanges in optical absorbance of the blood sample at severalwavelengths.

[0011] Dye-dilution measurements of cardiac output have been found to bedisadvantageous for several reasons. First, the necessity for continuousarterial blood withdrawal are time consuming, labor intensive anddeplete the patient of valuable blood. Second, the instruments used tomeasure dye concentrations (densitometer) must be calibrated withsamples of the patient's own blood containing known concentrations ofthe dye. This calibration process can be very laborious and timeconsuming in the context of the laboratory where several samples must berun on a daily basis. Further, technical difficulties arise inextracting the dye concentration from the optical absorbancemeasurements of the blood samples.

[0012] A variation on the dye-dilution technique is implemented in theNihon Kohden pulse dye densitometer. In this technique, blood absorbancechanges are detected through the skin with an optical probe (NihonKohden website: http://kohden.co.jp/intl/ppms-ddg2001.html) using avariation of pulse oximetry principles. This variation improves on theprior technique by eliminating the necessity for repeated bloodwithdrawal. However, as described above, this technique remains limitedby the difficulty of separating absorbance changes due to the dyeconcentration changes from absorbance changes due to changes in bloodoxygen saturation or blood content in the volume of tissue interrogatedby the optical probe. This method is also expensive in requiring largeamounts of dye to create noticeable changes in absorbance and a lightsource producing two different wavelengths of light for measuring lightabsorption by the dye and hemoglobin differentially. Even so, the highbackground levels of absorption in the circulatory system makes thistechnique inaccurate. Finally, where repeat measurements are desired,long intervals must ensue for the high levels of the indicator to clearfrom the blood stream. Thus, this technique is inconvenient for patientsundergoing testing and practitioners awaiting results to begin or altertreatment.

[0013] Other approaches for measuring cardiac output exist which are notbased on indicator dilution principles. These include ultrasoundDoppler, ultrasound imaging, the Fick principle applied to oxygenconsumption or carbon dioxide production and electric impedanceplethysmography (Darovic, supra). However, these techniques havespecific limitations. For instance, the ultrasound techniques (Dopplerand imaging) require assumptions on the three-dimensional shape of theimaged structures to produce cardiac output values from velocity ordimension measurements.

[0014] Blood volume measures the amount of blood present in thecardiovascular system. Blood volume is also a diagnostic measure whichis relevant to assessing the health of a patient. In many situations,such as during or after surgery, traumatic accident or in diseasestates, it is desirable to restore a patient's blood volume to normal asquickly as possible. Blood volume has typically been measured indirectlyby evaluating multiple parameters (such as blood pressure, hematocrit,etc.). However, these measures are not as accurate or reliable as directmethods of measuring blood volume.

[0015] Blood volume has been directly measured using indicator dilutiontechniques (Geddes, supra). Briefly, a known amount of an indicator isinjected into the circulatory system. After injection, a period of timeis allowed to pass such that the indicator is distributed throughout theblood, but without clearance of the indicator from the body. After theequilibration period, a blood sample is drawn which contains theindicator diluted within the blood. The blood volume can then becalculated by dividing the amount of indicator injected by theconcentration of indicator in the blood sample (for a more detaileddescription see U.S. Pat. 6,299,583 incorporated by reference). However,to date, the dilution techniques for determining blood volume aredisadvantageous because they are limited to infrequent measurement dueto the use of indicators that clear slowly from the blood.

[0016] Thus, it would be desirable to have a non-invasive, costeffective, accurate and sensitive technique for measuring cardiovascularparameters, such as cardiac output and blood volume.

INVENTION SUMMARY

[0017] The present invention is directed to methods and systems forassessing cardiovascular parameters within the circulatory system usingindicator dilution techniques. Cardiovascular parameters are anymeasures of the function or health of a subjects cardiovascular system.

[0018] In one aspect of the invention, a non-invasive method fordetermining cardiovascular parameters is described. In particular, anon-invasive fluorescent dye indicator dilution method is used toevaluate cardiovascular parameters. Preferably, the method is minimallyinvasive requiring only a single peripheral, intravenous line forindicator injection into the circulatory system of the patient. Further,it is preferable that only a single blood draw from the circulatorysystem of the patient be taken for calibration of the system, ifnecessary. Further, cardiovascular parameters may be evaluated bymeasuring physiological parameters relevant to assessing the function ofthe heart and circulatory system. Such parameters include, but are notlimited to cardiac output and blood volume.

[0019] Such minimally invasive procedures are advantageous over othermethods of evaluating the cardiovascular system. First, complicationsand patient discomfort caused by the procedures are reduced. Second,such practical and minimally invasive procedures are within thetechnical ability of most doctors and nursing staff, thus, specializedtraining is not required. Third, this minimally invasive methods may beperformed at a patient's bedside or on an out-patient basis. Finally,methods may be used on a broader patient population, including patientswhose low risk factors may not justify the use of central arterialmeasurements of cardiovascular parameters.

[0020] In another aspect of the invention, these methods may be utilizedto evaluate the cardiovascular parameters of a patient at a given momentin time, or repeatedly over a selected period of time. Preferably, thedosages of indicators and other aspects of the method can be selectedsuch that rapid, serial measurements of cardiovascular parameters may bemade. These methods can be well suited to monitoring patients havingcardiac insufficiency or being exposed to pharmacological interventionover time. Further, the non-invasive methods may be used to evaluate apatient's cardiovascular parameters in a basal state and when thepatient is exposed to conditions which may alter some cardiovascularparameters. Such conditions may include, but are not limited to changesin physical or emotional conditions, exposure to biologically activeagents or surgery.

[0021] In another aspect of the invention, modifications of the methodmay be undertaken to improve the measurement of cardiovascularparameters. Such modifications may include altering the placement of aphotodetector relative to the patient or increasing blood flow to thedetection area of the patient's body.

[0022] In another aspect of the invention, the non-invasive method ofassessing cardiovascular parameters utilizes detection of indicatoremission, that is fluorescence, as opposed to indicator absorption.Further, indicator emission may be detected in a transmission modeand/or reflection mode such that a broader range of patient tissues mayserve as detection sites for evaluating cardiovascular parameters, ascompared to other methods. Preferably, measurements of indicatoremission are more accurate than measurements obtained by other methods,as indicator emission can be detected directly and independent of theabsorption properties of whole blood.

[0023] In another aspect of the invention, a system for the non-invasiveor minimally invasive assessment of cardiovascular parameters isdescribed. In particular, such a system may include an illuminationsource for exciting the indicator, a photodetector for sensing emissionof electromagnetic radiation from the indicator and a computing systemfor receiving emission data, tracking data over time and calculatingcardiovascular parameters using the data.

[0024] In another aspect of the invention, the methods and systemdescribed herein may be used to assess cardiovascular parameters of avariety of subjects. In some embodiments, the methodology can bemodified to examine animals or animal models of cardiovascular disease,such as cardiomyopathies. The methodology of the present invention isadvantageous for studying animals, such as transgenic rodents whosesmall size prohibits the use of current methods using invasiveprocedures. The present invention is also advantageous in not requiringanesthesia which can affect cardiac output measurements.

[0025] In other embodiments, the methodology can be modified forclinical application to human patients. The present invention may beused on all human subjects, including adults, juveniles, children andneonates. The present invention is especially well suited forapplication to children, and particularly neonates. As above, thepresent technique is advantageous over other methods at least in that itis not limited in application by the size constraints of theminiaturized vasculature relative to adult subjects.

BRIEF DESCRIPTION OF THE DRAWINGS

[0026]FIG. 1 is a diagrammatic depiction of an example of one embodimentof the system of the present invention.

[0027]FIG. 2 is a fluorescence intensity curve generated using oneembodiment of the present invention.

[0028]FIG. 3 is a diagrammatic depiction of an example of one embodimentof the present invention having a photodetector positioned on the earskin surface.

[0029]FIG. 4 is a diagrammatic depiction of a user interface of acardiac output computer program useful in conjunction with thisinvention. The interface may depict information regarding valuesmeasured and converted from fluorescence to concentration, andparameters of the curve fit for the values obtained using the method orsystem.

[0030]FIG. 5 is a depiction of a decay of fluorescence intensity curveas a function of time following injection of a 1 mg dose of ICG.

[0031]FIG. 6 is a depiction of a calibration curve for blood ICGconcentration as a function of transcutaneous ICG fluorescence.

[0032]FIG. 7 is a depiction of cardiac output and aortic velocitymeasurements during one representative experiment.

[0033]FIG. 8 is a depiction of cardiac output measurements derived fromsites on the ear surface and on the exposed femoral artery during oneexperiment.

[0034]FIG. 9 is a flow chart depicting one method of the presentinvention.

DETAILED DESCRIPTION OF THE PREFERRED EMBODIMENTS

[0035] The method and system of the present invention are for theevaluation of cardiovascular parameters of a subject using an indicatordilution technique.

[0036] The method of this invention generally involves the injection ofa selected amount of indicator into the bloodstream of the subject (FIG.9). Preferably, the indicator is illuminated using a first wavelength ofexcitation light selected cause the indicator to fluoresce and emit asecond wavelength of light. A photodetector is placed near the subjectfor the detection of the intensity of the second wavelength of emittedlight which is proportional to the concentration of the indicatorcirculating within the circulatory system. The photodetector transmitsthis intensity information to a computing system, which records andpreferably maps the intensity curve of the indicator detected over time.

[0037] Typically, the indicator concentration values increase to a peakrapidly after injection of the indicator. Then, the concentration valuesdecrease rapidly, then more steadily as the indicator is diffusedthroughout the body and metabolized over time. A microprocessor drivencomputation then can calculate from the concentration curve, thepatient's cardiac output and/or blood volume values. Additionally,values can be generalized repeatedly using this method, at intervals ofabout every 1-2 minutes.

[0038] Indicators.

[0039] The indicators useful in this in invention are preferably inertand biocompatible in that they do not alter cardiovascular parameters,such as heart rate. Further, the indicator is preferably a substancethat once injected, does not diffuse out of the vasculature of thecardiovascular system. Also, the indicator is preferably selected to beone which is metabolized within the body at a rate such that repeatedmeasures using this method may be conducted at intervals of about 1-2minutes. It is also desirable that the background levels of circulatingindicator be cleared between intervals, although measurements may betaken when background levels are not zero. Finally, the indicator can beselected to be detectable by the photodetector system selected.

[0040] In one embodiment, a non-invasive dye indicator dilution methodmay be used to evaluate cardiovascular function function. Many differentdye indicators may be used within the scope of this invention.Preferably, the dye indicator is fluorescent having an excitationwavelength and an emission wavelength in the near infrared spectrum,preferably about 750 nm to about 1000 nm, and more preferably about 750nm to about 850 nm.

[0041] Most preferably, the indicator used is indocyanine green (ICG;purchased for example from Akorn, Decatur or Sigma, St. Louis, Mo.;commercial names: Diagnogreen©, ICGreen©, Infracyanine©, Pulsion©). ICGhas been previously been used to study the microcirculation of the eye,the digestive system and liver function (Desmettre, T., J. M.Devoisselle, and S. Mordon. Fluorescence properties and metabolicfeatures of indocyanine green (ICG) as related to angiography. SurvOphthalmol 45, 15-27, 2000). ICG fluoresces intensely when excited atnear infrared wavelengths. In the context of this invention, ICG inblood plasma has a peak fluorescence of about 810 to 830±10 nm with anoptimal excitation wavelength of about 780 nm (Hollins, supra; Dorshow,supra). ICG may be advantageous for use in this invention in remainsintravascular because it is protein bound. ICG breaks down quickly inaqueous solution, and metabolites are not fluorescent, minimizingrecirculation artifact and reducing the time period between whichmeasurements can be made. The wavelength of emission of ICG is alsowithin the optical window (750-1000 nm) in which living tissues arerelatively transparent to light.

[0042] Other biocompatible fluorescent dyes such as fluorescein andrhodamine would also be suitable in this invention. Fluorescein in bloodplasma has a peak fluorescence of about 518±10 nm with an optimalexcitation wavelength of about 488 nm (Hollins, supra; Dorshow, supra).Rhodamine in blood plasma has a peak fluorescence of about 640±10 nmwith an optimal excitation wavelength of about 510 nm.

[0043] Indicator Dosage.

[0044] The dosage of indicator is preferably selected such that anamount used is non-toxic to the subject, is present in the circulatorysystem for an amount of time adequate to establish an indicatorconcentration curve, but is metabolized in an amount of time such thatrepeated measurements can be conducted at intervals of about 1-2 minutesapart. Further, the indicator is preferably administered to the subjectby injection into a vein.

[0045] A dosage of about 0.005 mg/kg is preferable in that this doseleads to peak blood concentrations below 0.001 mg/ml. In thisconcentration range, the measurement of the circulating indicatorconcentration is linearly related to the intensity of the emissionwavelength detected. For example, in a laboratory animal model, about0.015 mg can be injected into a 3 kg rabbit (blood volume=200 ml) suchthat the average circulating concentration is about 0.000075 mg/ml wholeblood.

[0046] Dye dilution techniques have been applied in humans usingindocyanine green as a dye. Living tissues of humans and animals arerelatively transparent for near infrared wavelengths of light whichallows for transmission of light across several mm of tissue andtranscutaneous detection of the fluorescence emission of ICG. The use ofdosages in the ranges stated above is additionally suitable for humanuse.

[0047] Illumination Source.

[0048] The illumination sources useful in this invention are preferablyselected to produce an excitation wavelength in the near infraredspectrum, preferably about 750 nm to about 1 OOOnm, and more preferablyabout 750 to about 850 nm. This selection is advantageous in at leastthat most tissues are relatively transparent to wavelengths in thisrange. Thus, in some embodiments, an indicator in the blood stream isexcitable transcutaneously and indicator emission detectedtranscutaneously. Further, blood constituents do not fluoresce at thesewavelengths, thus there is no other contributor to the measuredfluorescence emission signal. Therefore, this method is advantageous inthat at least the sensitivity of detection in this method is improvedover other methods which measure indicator absorption, as opposed toemission.

[0049] However, it is within the scope of the invention to use otherwavelengths of light, for example in the blue-green or ultraviolet rangeas some tissues are relatively transparent even at these wavelengths.Selection of the illumination source, therefore, can depend in part onthe indicator selected and the tissue from which detection will be made.Preferably, the illumination source is selected to result in the peakemission wavelength of the indicator.

[0050] Examples of illumination sources which may be used in thisinvention include, but are not limited to lamps, light emitting diodes(LEDs), lasers or diode lasers.

[0051] In some embodiments, modifications to the system or illuminationsource may be altered to further to maximize the sensitivity or accuracyof the system for measuring indicator concentration. For example, insome embodiments, the excitation wavelength produced by the illuminationsource will be steady. Alternatively, the excitation wavelength producedby the illumination source can be modulated using a lock-in detectiontechnique (Stanford Research Systems website:http://www.srsys.com/html/scientific.html, herein incorporated byreference).

[0052] For example, the illumination source may emit light in a periodicvarying pattern having a fixed frequency and the emission recorded bythe photodetector read at the same frequency to improve the accuracy ofthe readings. The periodic varying pattern and frequency can be selectedto improve noise-rejection and should be selected to be compatible withthe rest of the instrumentation (such as the light source andphotodetector).

[0053] The illumination source may be adapted to target a detection areaof the subject's tissue from which emission wavelength intensity will berecorded. In some embodiments, the illumination source may comprise anoptic fiber for directing the excitation light to the detection area. Insome embodiments, the illumination source may comprise mirrors, filtersand/or lenses for directing the excitation light to the detection area.

[0054] Detection Areas.

[0055] The target detection area is that location of a subject's tissuewhich is exposed to the excitation wavelength of light and/or from whichthe emission wavelength light intensity output will be measured.

[0056] Preferably, the method of detection is non-invasive. In theseembodiments, a detection area is selected such that a photodetector canbe placed in proximity to the detection area and emission wavelengthlight intensity measured. Preferably, the photodetector is placedtransdermally to at least one blood vessel, but more preferably a highlyvascularized tissue area. Examples of detection areas include, but arenot limited to fingers, auricles of the ears, nostrils and areas havingnon-kertanized epithelium (such as the nasal mucosa or inner cheek). Inalternative embodiments, the method of detection is minimally invasive.For example, the photodetector can be placed subdermally (within orbeneath the epidermis) and proximate to at least one blood vessel or ina perivascular position. In yet alternative embodiments, the method ofdetection is invasive. For example, the photodetector can be placedintravascularly to detect indicator emission, such as within an artery.

[0057] Additionally, the detection area may be arterialized duringindicator emission detection. Examples of conditions resulting indetection area arterialization include, but are not limited to heatingor exposure to biologically active agents which effect sympatheticsystem blockade (such as lidocaine).

[0058] Photodetector.

[0059] The detection of indicator emission can be achieved by opticalmethods known in the art. Measurement of indicator concentration can bemade by administering a detectable amount of a dye indicator and using anon-invasive, minimally invasive or intravascular procedures, preferablyfor continuous detection. Preferably, the photodetector is positionedproximately to the detection area of the subject. The photodetector maybe positioned distally or proximately to the site of the illuminationsource.

[0060] In some embodiments, fluorescent light is emitted from theindicator with the same intensity for all directions (isotropy).Consequently, the emission of the dye can be detected both in“transmission mode” when the excitation light and the photodetector areon opposite sides of the illuminated tissue or in “reflection mode” whenthe excitation and the photodetector are on the same side of the tissue.This is advantageous over other methods at least in that the excitationlight and emitted light can be input and detected from any site on thebody surface and not only optically thin structures.

[0061] Photodetectors which are useful in this invention are thoseselected to detect the quantities and light wavelengths (electromagneticradiation) emitted from the selected indicator. Photodectors havingsensitivity to various ranges of wavelengths of light are well known inthe art.

[0062] In some embodiments, modifications to the system are made tofurther enhance the sensitivity or accuracy of the system for measuringindicator concentration. For example in some embodiments, the detectionsystem can incorporate a lock-in detection technique. For example, alock-in amplifier can be used to modulate the source of light emissionat a specific frequency and to amplify the output of the photodetectoronly at that frequency. This feature is advantageous in at least that itfurther improves the sensitivity of the system by reducing signal tonoise and allows detection of very small amounts of fluorescenceemission.

[0063] In some embodiments a photomultiplier tube is utilized as oroperably connected with another photodetector to enhance the sensitivityof the system. Finally, in some embodiments, additional features, suchas filters, may be utilized to minimize the background of the emissionsignals detected. For example, a filter may be selected whichcorresponds to the peak wavelength range or around the peak wavelengthrange of the indicator emission.

[0064] The detected electromagnetic radiation is converted intoelectrical signals by a photoelectric transducing device which isintegral to or independent of the photodetector. These electricalsignals are transmitted to a microprocessor which records the intensityof the indicator emission as correlated to the electrical signal for anyone time point or over time. (For an example of such a device see U.S.Pat. No. 5,766,125, herein incorporated by reference.)

[0065] System Calibration.

[0066] Preferably, the method is further minimally invasive in requiringonly a single peripheral blood draw from the circulatory system be takenfor calibration purposes. In this invention, indicator concentration ispreferably being measured continuously and non-invasively using aphotodetector. However, one blood sample from the subject may bewithdrawn for calibration of the actual levels of circulating indicatorwith the indicator levels detected by the system. For example, a bloodsample may be drawn from the subject at a selected time period after theadministration of the indicator into the blood stream. The blood samplemay then be evaluated for the concentration of indicator present bycomparison with a calibration panel of samples having known indicatorconcentrations. Evaluation of the indicator concentration may be madespectrophotometrically or by any other means known in the art. Where thesubject blood concentration of indicator falls within a range of about0.001 to about 0.002 mg/ml, the concentration-fluorescence curve islinear and it crosses the origin of the axes, that is the fluorescenceis zero when the concentration is zero. Therefore a single measurementpoint suffices to define the calibration curve, and no further bloodsamples need be taken.

[0067] More preferably no blood draw is required for calibration of thissystem. It is noted that the fluorescence of some indicators, such asICG, does not substantially vary from patient to patient and that theskin characteristics are relatively constant for large classes ofpatients. Thus, the fluorescence in the blood of the patient measuredfrom a given site on the body surface can be converted in an absolutemeasurement of ICG concentration, once the curve of indicatorconcentration vs. fluorescence is defined for that site of measurement.

[0068] This method and system may be utilized to measure severalcardiovascular parameters. Once the system has been calibrated to thesubject (where necessary) and the indicator emission detected andrecorded over time, the computing system may be used to calculatecardiovascular parameters including cardiac output and blood volume.

[0069] Cardiac Output Calculations.

[0070] In some embodiments, the cardiac output is calculated usingequations which inversely correlate the area under the first passindicator emission curve (magnitude of intensity curve) with cardiacoutput. Cardiac output is typically expressed as averages (L/min). Thegeneral methods have been previously described (Geddes, supra, hereinincorporated by reference).

[0071] Classically, the descending limb of the curve is plottedsemilogrithmically to identify the end of the first pass of indicator.For example, the descending limb of the curve may be extrapolated downto 1% of the maximum height of the curve. The curve can then becompleted by plotting values for times preceding the end time. Finally,the area under this corrected curve is established and divided by thelength (time) to render a mean height. This mean height is converted tomean concentration after calibration of the detector. The narrower thecurve, the higher the cardiac output; the wider the curve, the lower thecardiac output. Several variations of this calculation method are found,including methods that fit a model equation to the ascending anddescending portions of the indicator concentration curve.

[0072] Depending upon the indicator type and dosage selected, the curvemay not return to zero after the end of the first pass due to a residualconcentration of indicator recirculating in the system. Subsequentcalculations of cardiac output from the curve may then account for thisrecirculation artifact by correcting for the background emission, priorto calculating the area under the curve. This system is advantageousover the known methods in that at least the emission magnitude ofintensity is being directly measured and no measurement of hemoglobinnor accommodation for hemoglobin absorbance or need be made.

[0073] Results obtained using this system can be normalized forcomparison between subjects by expressing cardiac output as a functionof weight (CO/body weight (L/min/kg)) or as a function of surface area(cardiac index=CO/body surface area (L/min/m²)).

[0074] Blood volume calculations. In some embodiments, blood volume maybe measured independently or in addition to the cardiac output. Generalmethods of measuring blood volume are known in the art. In someembodiments, circulating blood volume may be measured using a low doseof indicator which is allowed to mix within the circulatory system for aperiod of time selected for adequate mixing, but inadequate or theindicator to be completely metabolized. The circulating blood volume maythen be calculated by back extrapolating to the instant of injection theslow metabolic disappearance phase of the concentration curve detectedover time (Bloomfield, D. A. Dye curves: The theory and practice ofindicator dilution. University Park Press, 1974). Alternative methods ofcalculation include, but are not limited to those described in U.S. Pat.Nos. 5,999,841, 6,230,035 or 5,776,125, herein incorporated byreference.

[0075] This method and system may be used to examine the generalcardiovascular health of a subject. In one embodiment, the method may beundertaken one time, such that one cardiac output and or blood volumemeasurement would be obtained. In other embodiments, the method may beundertaken to obtain repeated or continuous measurements ofcardiovascular parameters over time. Further, repeated measures may betaken in conditions where the cardiovascular system is challenged suchthat a subject's basal and challenged cardiovascular parameters can becompared. Challenges which may be utilized to alter the cardiovascularsystem include, but are not limited to exercise, treatment withbiologically active agent which alter heart function (such asepinephrine), parasympathetic stimulation (such as vagal stimulation),injection of liquids increasing blood volume (such as colloidal plasmasubstitutes) or exposure to enhanced levels of respiratory gases.

[0076] A schematic of one embodiment of a system 10 useful in thepresent invention is shown in FIG. 1. The system comprises anillumination source 12 here a 775 nm laser selected to emit a excitationwavelength of light 14 which maximally excites ICG, the indicatorselected. Here the illumination source 12 is positioned proximately tothe subject 16, such that the excitation wavelength of light 14 shinestransdermally onto the indicator circulating in the bloodstream. Thesystem also comprises a photodetector 20 placed in proximity to thesubject's skin surface 18 for detection of the indicator emissionwavelength 22. Optionally, a filter 24 may be used for isolating thepeak wavelength at which the indicator emits, being about 830 nm.Finally, the photodetector 20 is operably connected to a microprocessor26 for storing the electronic signals transmitted from the photodetector20 over time, and generating the indicator concentration curve (FIG. 2).Optionally, the microprocessor 26 may regulate the illumination sourceto coordinate the excitation and detection of emission from theindicator, for example using a modulation technique. The microprocessormay also comprise software programs for analyzing the output obtainedfrom the detector 20 such that the information could be converted intovalues of cardiac output or blood volume, for example and/or displayedin the form of a user interface.

[0077] In order to demonstrate the utility of the invention, anon-invasive indicator detection system 10 of the invention was used torepeatedly monitor cardiac output. With reference to FIG. 1, a fiberoptic 12 b transmitted light from illumination source 12 a to thesubject's skin 18. A second fiber optic 20 b, positioned near the skin18 transmitted the emitted light to a photodetector 20. The indicatorwas intravenously injected. A body portion which included blood vesselsnear the surface of the skin, was irradiated with a laser. Acharacteristic fluorescence intensity/concentration curve was obtainedupon excitation with laser light at about 775 nm and detection of thefluorescence at about 830 nm. From this information cardiac output andblood volume for the subject was calculated.

[0078] The system used for this method may comprise a variety ofadditional components for accomplishing the aims of this invention. Forexample, non-invasive detection is described for monitoring ofindicators within the circulatory system of the patient. Modificationsof the detectors to accommodate to various regions of the patient's bodyor to provide thermal, electrical or chemical stimulation to the bodyare envisioned within the scope of this invention. Also, calibration ofthe system may be automated by a computing system, such that a bloodsample is drawn from the patient after administration of the indicator,concentration detected and compared with known standards and/or theemission curve. Also, software may be used in conjunction with themicroprocessor to aid in altering parameters of any of the components ofthe system or effectuating the calculations of the cardiovascularparameters being measured. Further, software may be used to displaythese results to a user by way of a digital display, personal computeror the like.

[0079] The utility of the invention is further illustrated by thefollowing examples, which are not intended to be limiting.

EXAMPLE 1

[0080] Experimental system and method. An implementation of the systemand method of this invention was tested in rats. The excitation sourcewas a 775 nm pulsed diode laser and the fluorescence was detected with adetector being a photomultiplier (PMT) with extended response in thenear-infrared range of the spectrum (FIG. 1). Optic fibers were placedin close contact with the skin of the animal's ear for the excitationand detection of the indicator within the blood stream. After injectionof a 100 μl bolus of ICG (0.0075 mg/ml) into the jugular vein of a rat,the fluorescence intensity trace (indicator concentration recording) wasmeasured transcutaneously at the level of the rat's ear using reflectionmode detection of emission (FIG. 2).

[0081] Calculation of Blood Volume and Cardiac Output.

[0082] The initial rapid rise and rapid decay segments of thefluorescence intensity trace represent the first pass of the fluorescentindicator in the arterial vasculature of the animal. Such a waveform ischaracteristic of indicator dilution techniques. This portion of therecording is analyzed with one of several known algorithms (i.e. StewartHamilton technique) to compute the “area under the curve” of thefluorescence intensity trace while excluding the recirculation artifact.Here, the initial portion of the fluorescence trace y(t) was fitted witha model equation y(t)=y₀t^(α)exp(−βt) which approximates both the risingand descending segments of the trace. This equation derived from a“tank-in-series” representation of the cardiovascular system has beenfound fit well the experimental indicator dilution recordings. Thenumerical parameters of the fit were determined from the approximationprocedure, and then the “area under the curve” was computed by numericintegration and used to find the cardiac output with the known formula:$Q\underset{\infty_{0}}{=}{\frac{m}{{C(t)}d\quad t} = \frac{\text{amount~~injected}}{\text{area~~under~~the~~curve}}}$

[0083] Back extrapolation of the slow decay segment of the fluorescenceintensity trace to the instant when ICG is first detected in the blood(time 0) yields the estimated concentration of ICG mixed in the wholecirculating blood volume. By dividing the amount of injected ICG by thisextrapolated ICG concentration at time 0, the circulating blood volumewas computed.

[0084] Calibration Methods.

[0085] Indicator concentration C(t) was computed from the fluorescencey(t) using one of two calibration methods. Transcutaneous in vivofluorescence was calibrated with respect to absolute bloodconcentrations of ICG, using a few blood samples withdrawn from aperipheral artery after bolus dye injection of ICG. The blood sampleswere placed in a fluorescence cell and inserted in a tabletopfluorometer for measurement of their fluorescence emission. Thefluorescence readings were converted into ICG concentrations using astandard calibration curve established by measuring with the tabletopfluorometer the fluorescence of blood samples containing knownconcentrations of ICG.

[0086] An alternative calibration procedure which avoids blood loss usesa syringe outfitted with a light excitation—fluorescence detectionassembly. The syringe assembly was calibrated once before the cardiacoutput measurements by measuring ICG fluorescence in the syringe fordifferent concentrations of ICG dye in blood contained in the barrel ofthe syringe. During the measurement of cardiac output, a blood samplewas pulled in the syringe during the slow decay phase of thefluorescence trace, that is the phase during which recirculating dye ishomogeneously mixed in the whole blood volume and is being slowlymetabolized. The fluorescence of that sample was converted toconcentration using the syringe calibration curve and then related tothe transcutaneous fluorescence reading. So long as the ICGconcentrations in blood remain sufficiently low (<0.001 mg/ml), a linearrelationship can be used to relate fluorescence intensity toconcentration.

[0087] Either one of these calibration methods can be developed on areference group of subjects to produce a calibration nomogram that wouldserve for all other subjects with similar physical characteristics(i.e., adults, small children etc.). This is advantageous over priormethods at least in that an additional independent measurement of theblood hemoglobin concentration for computation of the light absorptiondue to hemoglobin is not required.

EXAMPLE 2

[0088] A. A Sample Method and System for Measuring Cardiac Output andBlood Volume.

[0089] Experiments have been performed in New Zealand White rabbits(2.8-3.5 Kg) anesthetized with halothane and artificially ventilatedwith an oxygen-enriched gas mixture (FiO2 ˜0.4) to achieve a Sa 2 above99% and an end-tidal CO2 between 28 and 32 mm Hg (FIG. 4). The leftfemoral artery was cannulated for measurement of the arterial bloodpressure throughout the procedure. A small catheter was positioned inthe left brachial vein to inject the indicator, ICG. Body temperaturewas maintained with a heat lamp.

[0090] Excitation of the ICG fluorescence was achieved with a 780 nmlaser (LD head: Microlaser systems SRT-F780s⁻¹²) whose output wassinusoidally modulated at 2.8 KHz by modulation of the diode current atthe level of the laser diode driver diode (LD Driver: Microlaser SystemsCP 200) and operably connected to a thermoelectric controller(Microlaser Systems: CT15W). The near-infrared light output wasforwarded to the animal preparation with a fiber optic bundle terminatedby a waterproof excitation-detection probe. The fluorescence emitted bythe dye in the subcutaneous vasculature was detected by the probe anddirected to a 830 nm interferential filter (Optosigma 079-2230) whichpassed the fluorescence emission at 830±10 nm and rejected theretro-reflected excitation light at 780 nm. The fluorescence intensitywas measured with a photomultiplier tube (PMT; such as HamamatsuH7732-10MOD) connected to a lock-in amplifier (Stanford Research SR 510)for phase-sensitive detection of the fluorescence emission at thereference frequency of the modulated excitation light. The output of thelock-in amplifier was displayed on a digital storage oscilloscope andtransferred to a computer for storage and analysis.

[0091] In most experiments, one excitation-detection probe waspositioned on the surface of the ear arterialized by local heating. Insome studies, the laser emission beam was separated in two beams with abeam splitter and directed to two measurement sites (ear skin andexposed right femoral artery). Two detection systems (PMT+lock inamplifier) were used for measurement of the fluorescence dilution tracesfrom the two sites. In all experiments, a complete record of allexperimental measurements (one or two fluorescence traces, arterialblood pressure, end-tidal CO2 , Doppler flow velocity) was displayed online and stored for reference.

[0092] Calculations. A LabView program was used to control theoscilloscope used for sampling the fluorescence dilution curves,transfer the data from the oscilloscope to a personal computer andanalyze the curves online for estimation of the cardiac output andcirculating blood volume. As shown on the program user interface (FIG.5), the measured fluorescence dilution trace (a) is converted to ICGblood (b) using the calibration parameters estimated as described in thenext section of this application and fitted to a model:C(t)=C₀t^(α)exp(−βt).

[0093] The model fit (white trace) is performed from the time point forwhich the fluorescent ICG is first detected to a point on the decayingportion of the trace that precedes the appearance of recirculatingindicator (identified from the characteristic hump after the initialpeak in the experimental trace). The model equation is used to estimatethe “area under the curve” for the indicator dilution trace. The theoryof indicator dilution technique predicts that the area under theconcentration curve is inversely proportional to the cardiac output (Q):m/^(∞) ₀ C(t)dt.

[0094] where m is the mass amount of injected indicator and C(t) is theconcentration of indicator in the arterial blood at time t. The programalso fits the slow decaying phase of the measurement to a singleexponential to derive the circulating blood volume from the value of theexponential fit at the time of injection. For the experimental ICG traceshown in FIG. 4, the estimated cardiac output is 509 ml/min and thecirculating blood volume is 184 ml, in the expected range for a 3 Kgrabbit. This computer program is advantageous in that it improved theability to verify that the experimental measurements are proceeding asplanned or to correct without delay any measurement error orexperimental malfunction.

[0095] Indicator Dosage.

[0096] In this experiment is was found that a dose of about 0.015 mginjected ICG was optimal in this animal to allow for detection of anintense fluorescence dilution curve and at the same time rapid metabolicdisposal of the ICG. Further, with this small dose cardiac functionmeasurements could be performed at about intervals of less than aboutevery 4 minutes.

[0097] Detector Placement.

[0098] Defined fluorescence readings were obtained by positioning thedetection probe above the skin surface proximate to an artery or abovetissue, such as the ear or the paw arterialized by local heating.

[0099] B. Calibration of Transcutaneous Indicator Intensity andCirculating Indicator Concentration.

[0100] Calibration of the transcutaneous fluorescence intensity measuredat the level of the animals' ear as a function of ICG concentration inblood was performed as follows. A high dose of ICG (1 mg) was injectedintravenously and equilibrated homogeneously with the animal's totalblood volume in about a one minute period. At equilibrium, the blood ICGconcentration resulting from this high dose is several times larger thanthe peak ICG concentration observed during the low dose ICG injections(0.015 mg) used to measured cardiac output. In this way, a calibrationcurve was created that accommodated the full range of ICG concentrationsobserved during the cardiac function measurements.

[0101] As the liver metabolizes ICG, the blood ICG concentrationdecreases back to 0 in about 20 minutes. During that time period, 5 to 8blood samples (1.5 ml) were withdrawn from the femoral artery and placedin a precalibrated blood cuvette. The fluorescence intensity of theblood in the cuvette was converted to a measurement of concentrationusing the known standard curve of fluorescence intensity versus ICGconcentration established for the cuvette. ICG fluorescence was measuredat the level of the ear at the exact time of the blood samplewithdrawal. Because ICG is homogeneously equilibrated in the animal'sblood volume, when the blood samples are withdrawn, the fluorescenceintensity measured at the level of the ear corresponds directly to theICG blood concentration at the time of the measurement and therefore theICG concentration determined from the cuvette reading. As this exampleshows, transcutaneous ICG fluorescence is proportional to blood ICGconcentration such that a single blood withdrawal can suffice to findthe proportionality factor between the two quantities.

[0102] As shown in FIG. 5, the transcutaneous ear fluorescence intensity(in V) as a function of time (in s) after the high dose (1 mg) ICGinjection during the calibration sequence. FIG. 5 shows thecharacteristic first order exponential decay of ICG in blood as the dyeis being metabolized. FIG. 6 shows the ICG concentration (in mg/ml) as afunction of the in vivo fluorescence for the same example and the sametime points. For the range of concentrations used in these studies, ICGconcentration and transcutaneous fluorescence were linearly related. Thecalibration line passes through the origin of the axes since there is nomeasured fluorescence when the ICG blood concentration is 0.

[0103] Thus, a simple proportionality factor exists between blood ICGconcentration and transcutaneous fluorescence. This feature of thefluorescence dilution technique measuring light emission is advantageousover the conventional dye dilution technique based on ICG absorptionwhich requires light absorption caused by ICG to be separated from lightabsorption by tissue and blood. After the proportionality factor isdetermined, ICG fluorescence dilution profiles can only then beconverted into concentration measurement for computation of the cardiacoutput using the indicator-dilution equation.

[0104] Results of Cardiac Output Measurements.

[0105] Calibrated cardiac output readings have been obtained in 5animals (body wt: 3.0±0.2 Kg). The following table lists the valuesduring baseline conditions. The values are presented as themean±standard deviation of three consecutive measurements obtainedwithin a 15 min period. TABLE 1 Exp. Cardiac output (ml/min) 1 530 ± 152 500 ± 17 3 370 ± 12 4 434 ± 16 5 481 ± 6 

[0106] The average for the five experiments (463 ml/min) is in order ofreported cardiac outputs (260-675 ml/min) measured with ultrasound orthermodilution techniques in anesthetized rabbits (Preckel et al. Effectof dantrolene in an in vivo and in vitro model of myocardial reperfusioninjury. Acta Anaesthesiol Scand, 44,194-201, 2000. Fok et al. Oxygenconsumption by lungs with acute and chronic injury in a rabbit model.Intensive Care Med, 27, 1532-1538, 2001). Basal cardiac output variesgreatly with experimental conditions such as type of anesthetic,duration and depth of anesthesia, leading to the wide range of valuesfound in the literature. In this example, the variability (standarddeviation/mean) of the calculated cardiac output with fluorescencedilution is ˜3% for any triplicate set of measurements which comparesfavorably with the reported variability for the thermodilution technique(˜5-10%).

[0107] C. Comparison of Measurements Obtained by Fluorescence DilutionCardiac Output Method via Transcutaneous Measurement and SubcutaneousMeasurement.

[0108] Experimental Methodology.

[0109] The experimental preparation described in the preceding section(Example 2) includes two measurement sites for the fluorescence dilutiontraces: a transcutaneous site at the level of the ear central bundle ofblood vessels and the exposed femoral artery. The ear vasculature isarterialized by local heating. With this preparation, the cardiac outputestimates obtained from the peripheral non-invasive (transcutaneous)measurement site were compared with estimates obtained by interrogatinga major artery.

[0110] The intensity of the fluorescence signal at the level of theexposed femoral artery during the slow metabolic disappearance phase ofthe injected ICG is compared to the calibrated ear fluorescencemeasurement to derive a calibration coefficient (arterial ICGfluorescence into ICG blood concentration). In this way cardiac outputestimates expressed in ml/min were derived from the two sites.

[0111] Results.

[0112]FIG. 8 shows the time course of the cardiac output measurementsobtained from the ear site and from the exposed femoral artery in arepresentative experiment during control conditions (C), intense thenmild vagal stimulation (S,I and S,M), and post-stimulation hyperemia(H). Near-identical estimates of the cardiac output are obtained fromthe two sites during all phases of the study.

[0113] The relationship between cardiac output derived from measurementof the fluorescence dilution curve at the level of the skin surface(COskin, in ml/min) and at the level of the exposed femoral artery(COfem, in ml/min) was investigated. The linear relationships betweenthe two measures are summarized in the table below: TABLE 2 RegressionNumber Exp. Linear regression Coef. measurements 1 Co_(skin) =0.65(±0.11)^(*) Co_(fem) + 145.0(±54.0) 0.81 22 2 Co_(skin) =1.01(±0.06)^(*) Co_(fem) + 2.0(±22.0) 0.96 27 3 Co_(skin) =1.05(±0.14)^(*) Co_(fem) − 56.0(±54.0) 0.91 13

[0114] The two measures of fluorescence cardiac output are tightlycorrelated. In the last two experiments, the slope of the regressionline is not statistically different from 1.0 and the ordinate is notdifferent from 0.0 indicating that the two measurements are identical.These observations suggest that fluorescence dilution cardiac output canbe reliably measured transcutaneously and from a peripheral site ofmeasurement that has been arterialized by local application of heat.Attenuation of the excitation light and ICG fluorescence emission by theskin does not prevent the measurement of well-defined dye dilutiontraces that can be analyzed to derive the cardiac output.

[0115] While the specification describes particular embodiments of thepresent invention, those of ordinary skill can devise variations of thepresent invention without departing from the inventive concept.

[0116] D. Comparison of Measurements Obtained by Fluorescence DilutionCardiac Output Method and Doppler Flow Velocity Technique.

[0117] Experimental Methodology.

[0118] The present method was compared with an ultrasonic Dopplervelocity probe method to record cardiac output measurements. In thisexample the above procedure was modified in that, the animal's chest wasopened with a median incision of the sternum and a 6 mm 20 MHz Dopplervelocity probe was gently passed around the ascending aorta andtightened into a loop that fits snuggly around the aorta.

[0119] For detection of the fluorescent detection of the indicator, twoillumination +detection fiber optic probes were used: one probe wasplaced on or above the ear middle vessel bundle and the other probe wasplaced in proximity to the dissected left femoral artery. Local heatingto 44 degrees centigrade arterialized the ear vasculature.

[0120] In this example, two maneuvers were used to change the cardiacoutput from its control level: vagal stimulation, which reduces thecardiac output, and saline infusion, which increases the circulatingvolume and cardiac output. The right vagal nerve was dissected toposition a stimulating electrode. Stimulation of the distal vagusresults in a more or less intense decrease of the heart rate thatdepends on the stimulation frequency and voltage (1 ms pulses, 3 to 6 V,10 to 30 Hz). The cardiac output and aortic flow velocity also decreaseduring vagal stimulation even though less markedly than the heart ratedecreases because the stroke volume increases. Saline infusion at a rateof 15-20 ml/min markedly increases the cardiac output. FIG. 7 shows thetime course of the cardiac output and aortic velocity measurements inone experiment including control conditions (C), intense then mild vagalstimulation (S,I and S,M), and saline infusion (I).

[0121] Results.

[0122] There is consistent tracking of the Doppler aortic velocity bythe fluorescence dilution cardiac output measurement. The relationshipbetween fluorescence dilution cardiac output and aortic Doppler flowvelocity was investigated in four rabbits. The linear relationshipsbetween fluorescence dilution cardiac output (CO, in ml/min) and aorticflow velocity signal (VAor, not calibrated, in Volts) are summarized inthe table: TABLE 3 Regression Exp. Linear regression Coef. Measurements1 CO = 789(±123)^(*) VA_(or) + 166(±34) 0.79 27 2 CO = 607(±62)^(*)VA_(or) + 50(±32) 0.90 24 3 CO = 614(±64)^(*) VA_(or) − 45(±38) 0.90 274 CO = 654(±41)^(*) VA_(or) − 3(±29) 0.97 18

[0123] This data indicates that the fluorescence dilution cardiac outputis highly correlated with aortic flow velocity as indicated by theelevated regression coefficient (≧0.9 in 3 experiments). Further, theslopes of the linear regression lines between fluorescence dilutioncardiac output and aortic flow velocity are similar and statisticallynot different in the four studies. This suggests a constant relationshipbetween the two variables across experiments. The ordinates ofregression lines are not different from 0 in the last three experimentalstudies, which suggests absence of bias between the two measures ofaortic flow.

[0124] The results above establish that fluorescence dilution cardiacoutput measured transcutaneously tracks the Doppler flow velocitymeasured in the ascending aorta.

We claim:
 1. A method of measuring at least one parameter of thecardiovascular system of a subject comprising: a. administering to thecirculatory system of a subject a detectable amount of at least oneindicator; b. applying a first wavelength of light for exciting theindicator within the cardiovascular system and causing the indicator toemit a second wavelength of light, c. detecting the magnitude ofintensity of the second wavelength of light emitted from the indicatorin the circulatory system using at least one photodetector proximatelylocated to a detection area of the subject; d. analyzing mathematicallythe detected magnitude of intensity of the second wavelength of light tocompute at least one parameter of the cardiovascular system of thesubject.
 2. The method of claim 1 wherein the second wavelength of lightemitted from the indicator is caused by fluorescence of the indicator.3. The method of claim 1 further including calibrating the measurementof the one parameter of the cardiovascular system of a subject byremoving a blood sample containing indicator from the subject, applyinga first wavelength of light for exciting the indicator within the bloodsample, detecting the intensity of a second wavelength of light emittedfrom the blood sample, comparing the intensity of the second wavelengthof light emitted from the blood sample to the intensity of the secondwavelength of light emitted from the indicator in the circulatorysystem.
 4. The method of claim 1 wherein the measured parameter of thecardiovascular system is cardiac output and wherein the method furthercomprises detecting the magnitude of intensity of the second wavelengthof light emitted from the indicator over a time period, forming amagnitude of intensity curve for the time period, and wherein themathematical analysis of cardiac output comprises at least one of curvefitting to a model equation or numerical integration.
 5. The method ofclaim 4 further comprising calculating the cardiac index by expressingthe cardiac output as a function of either the subject's weight or thesubjects surface area.
 6. The method of claim 1 wherein the measuredparameter of the cardiovascular system is circulating blood volume andwherein the method further comprises detecting the magnitude ofintensity of the second wavelength of light emitted from the indicatorover a time period, forming a magnitude of intensity curve for the timeperiod, and wherein the mathematical analysis of blood volume comprisesback extrapolating a slow phase of the intensity curve to determinecirculating blood volume.
 7. The method of claim 1, wherein thephotodetector is placed in at least one of a transdermal detection area,a subdermal detection area, a perivascular detection area or anendovascular detection area.
 8. The method of claim 1, wherein thedetecting is performed in either transmission mode or reflection mode.9. The method of claim 1, wherein steps a-d are repeated at a timeinterval to determine if the cardiovascular value for the subject haschanged.
 10. The method of claim 1, further comprising treating thepatient with a stimulus and wherein steps a-d are repeated at a timeinterval to determine if the cardiovascular value for the subject haschanged after exposure to the stimulus.
 11. The method of claim 1wherein the detection area is arterialized by application of heat orpharmacologically prior to detecting the second wavelength of light atthe detection area.
 12. The method of claim 1 wherein the firstwavelength of light is within the range of about 750 nm to about 1000nm.
 13. The method of claim 1 wherein the indicator is a chromophore orfluorophore emitting the second wavelength of light in a range fromabout 400 nm to about 1000 nm.
 14. The method of claim 1 wherein thefluorophores are selected from the group comprising indocyanine green,fluorescein and rhodamine.
 15. A method of measuring at least oneparameter of the cardiovascular system of a subject comprising:administering to the circulatory system of a subject a detectable amountof at least one indicator; applying a first wavelength of light forexciting the indicator within the cardiovascular system and causing theindicator to emit a second wavelength of light within the range of about750 nm to about 1000 nm, detecting the magnitude of intensity of thesecond wavelength of light emitted from the indicator in the circulatorysystem using at least one photodetector proximately located to adetection area of the subject; analyzing mathematically the detectedmagnitude of intensity of the second wavelength of light to compute atleast one parameter of the cardiovascular system of the subject.
 16. Themethod of claim 15 wherein the measured parameter of the cardiovascularsystem is cardiac output and wherein the method further comprisesdetecting the magnitude of intensity of the second wavelength of lightemitted from the indicator over a time period, forming a magnitude ofintensity curve for the time period, and wherein the mathematicalanalysis of cardiac output comprises at least one of curve fitting to amodel equation or numerical integration.
 17. The method of claim 16further comprising calculating the cardiac index by expressing thecardiac output as a function of either the subject's weight or thesubjects surface area.
 18. The method of claim 15 wherein the measuredparameter of the cardiovascular system is circulating blood volume andwherein the method further comprises detecting the magnitude ofintensity of the second wavelength of light emitted from the indicatorover a time period, forming a magnitude of intensity curve for the timeperiod, and wherein the mathematical analysis of blood volume comprisesback extrapolating a slow phase of the intensity curve to determinecirculating blood volume.
 19. The method of claim 15, wherein thephotodetector is placed in at least one of a transdermal detection area,a subdermal detection area, a perivascular detection area, or anendovascular detection area.
 20. The method of claim 15, wherein thedetecting is performed in either transmission mode or reflection mode.21. The method of claim 15, wherein steps a-d are repeated at a selectedinterval to determine if the cardiovascular value for the subject haschanged.
 22. The method of claim 15, further comprising treating thepatient with a stimulus and wherein steps a-d are repeated at a selectedinterval to determine if the cardiovascular value for the subject haschanged after exposure to the stimulus.
 23. The method of claim 15wherein the detection area is arterialized by application of heat orpharmacologically prior to detecting the second wavelength of light atthe detection area.
 24. A system for determining parameters of thecardiovascular system of a subject comprising: an illumination sourceconfigured to be positioned proximately to at least one blood vessel ofthe cardiovascular system for providing a first wavelength of light forexciting an indicator within the cardiovascular system and causing theindicator to emit a second wavelength of light; a photodetectorconfigured to be positioned proximate to at least one blood vessel ofthe cardiovascular system of the subject for detecting the magnitude ofintensity of the second wavelength of light emitted from the indicatorin the circulatory system and for transmitting electronic signalsproportionate to the detected magnitude of intensity of the secondwavelength of light to a computing system; the computing system forreceiving the electronic signals and analyzing mathematically thedetected magnitude of intensity to compute at least one parameter of thecardiovascular system of the subject.
 25. The system of claim 24 furthercomprising at least one fiber optic probe operably connected to theillumination source for guiding the first wavelength of light from theillumination source to the detection area.
 26. The system of claim 24further comprising at least one fiber optic probe operably connected tothe photodetector for guiding the second wavelength of light from thedetection area to the photodetector.
 27. The system of claim 24 furthercomprising at least one lock-in amplifier operably connected to theillumination source for modulating the first wavelength of light at aselected frequency, and operably connected to the photodetector forfiltering the detection of the second wavelength of light at theselected frequency.
 28. The system of claim 24 wherein the measuredparameter of the cardiovascular system is cardiac output and wherein themethod further comprises detecting the magnitude of intensity of thesecond wavelength of light emitted from the indicator over a timeperiod, forming a magnitude of intensity curve for the time period, andwherein the mathematical analysis of cardiac output comprises at leastone of curve fitting to a model equation or numerical integration. 29.The method of claim 28 further comprising calculating the cardiac indexby expressing the cardiac output as a function of either the subject'sweight or the subjects surface area.
 30. The method of claim 24 whereinthe measured parameter of the cardiovascular system is circulating bloodvolume and wherein the method further comprises detecting the magnitudeof intensity of the second wavelength of light emitted from theindicator over a time period, forming a magnitude of intensity curve forthe time period, and wherein the mathematical analysis of blood volumecomprises back extrapolating a slow phase of the intensity curve todetermine circulating blood volume.
 31. The system of claim 24, whereinthe photodetector is configured for placement in at least one of atransdermal detection area, a subdermal detection area, a perivasculardetection area or an endovascular detection area.
 32. The system ofclaim 24 wherein the first wavelength of light is in the range of about750 nm to about 1000 nm.
 33. The system of claim 24 wherein theindicator is a chromophore or fluorophore capable of emitting the secondwavelength of light in a range from about 400 nm to about 1000 nm.